title: Genetic variability of the mTOR pathway and prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).
abstract: The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p<0.01) and sought to replicate their association in an additional series of 838 prostate cancer cases and 943 controls from EPIC. In the joint analysis of first and second phase two SNPs of the PRKCI gene showed an association with risk of prostate cancer (OR(allele) = 0.85, 95% CI 0.78-0.94, p = 1.3 x 10⁻³ for rs546950 and OR(allele) = 0.84, 95% CI 0.76-0.93, p = 5.6 x 10⁻⁴ for rs4955720). We confirmed this in a meta-analysis using as replication set the data from the second phase of our study jointly with the first phase of the Cancer Genetic Markers of Susceptibility (CGEMS) project. In conclusion, we found an association with prostate cancer risk for two SNPs belonging to PRKCI, a gene which is frequently overexpressed in various neoplasms, including prostate cancer.
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.forename: Anika
authors.initials: A
authors.lastname: Hüsing
authors.forename: Angelika
authors.initials: A
authors.lastname: Stein
authors.forename: Lucie
authors.initials: L
authors.lastname: Dostal
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Tobias
authors.initials: T
authors.lastname: Pischon
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Nina
authors.initials: N
authors.lastname: Roswall
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Jane Nautrup
authors.initials: JN
authors.lastname: Østergaard
authors.forename: Laudina
authors.initials: L
authors.lastname: Rodríguez
authors.forename: Núria
authors.initials: N
authors.lastname: Sala
authors.forename: Maria-José
authors.initials: MJ
authors.lastname: Sánchez
authors.forename: Nerea
authors.initials: N
authors.lastname: Larrañaga
authors.forename: José María
authors.initials: JM
authors.lastname: Huerta
authors.forename: Aurelio
authors.initials: A
authors.lastname: Barricarte
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wareham
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Allen
authors.forename: Pagona
authors.initials: P
authors.lastname: Lagiou
authors.forename: Antonia
authors.initials: A
authors.lastname: Trichopoulou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Sabina
authors.initials: S
authors.lastname: Sieri
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.forename: Henk
authors.initials: H
authors.lastname: van Kranen
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.forename: Isabelle
authors.initials: I
authors.lastname: Romieu
authors.forename: Mazda
authors.initials: M
authors.lastname: Jenab
authors.forename: David G
authors.initials: DG
authors.lastname: Cox
authors.forename: Afshan
authors.initials: A
authors.lastname: Siddiq
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
mesh_terms: D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005060:Europe; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000502:physiology; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C; D058570:TOR Serine-Threonine Kinases; D000099293:Protein Kinase C-lambda; C546842:MTOR protein, human